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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1662-1672. Prepublished online as a Blood First Edition Paper on June 23, 2008; DOI 10.1182/blood-2008-01-128413. This Article Full Text (PDF) All Versions of this Article: blood-2008-01-128413v1 112/5/1662    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Peng, B. Articles by Miao, C. H. Search for Related Content PubMed PubMed Citation Articles by Peng, B. Articles by Miao, C. H. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 31, 2008 Accepted June 8, 2008 Transient blockade of the inducible costimulator pathway generates long-term tolerance for factor VIII following nonviral gene transfer into hemophilia A mice Baowei Peng, Peiqing Ye, Bruce R. Blazar, Gordon J. Freeman, David J. Rawlings, Hans D. Ochs, and Carol H. Miao* Department of Pediatrics, Seattle Children's Hospital Research Institute and University of Washington, Seattle, WA, United States Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, United States * Corresponding author; email: miao{at}u.washington.edu. Formation of inhibitory antibodies is a common problem encountered following replacement therapy in the treatment of hemophilia A patients. Human factor VIII (hFVIII) plasmid gene therapy in hemophilia A mice also leads to strong humoral responses. We demonstrate that short-term therapy with an anti-ICOS mAb to transiently block the ICOS/ICOSL signaling pathway led to sustained tolerance to hFVIII in hemophilia A mice treated with hFVIII plasmid and allowed persistent, high-level FVIII functional activity (100-300% of normal). Anti-ICOS treatment resulted in depletion of ICOS+CD4+ T cells and activation of CD25+Foxp3+ Tregs in the peripheral blood, spleen, and lymph nodes. CD4+ T cells from anti-ICOS-treated mice did not proliferate in response to hFVIII stimulation and produced high levels of regulatory cytokines including IL-10 and TGF-. Moreover, CD4+CD25+ Tregs from tolerized mice adoptively transferred dominant tolerance in syngeneic hFVIII plasmid-treated hemophilia A mice, and reduced the production of antibodies against FVIII. Anti-ICOS-treated mice tolerized to hFVIII generated normal primary and secondary antibody responses following immunization with the T dependent antigen, bacteriophage x174, indicating maintenance of immune competency. Our data indicate that transient anti-ICOS mAb treatment represents a novel single agent immunomodulatory strategy to overcome the immune responses against transgene product following gene therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Peng, P. Ye, D. J. Rawlings, H. D. Ochs, and C. H. Miao Anti-CD3 antibodies modulate anti-factor VIII immune responses in hemophilia A mice after factor VIII plasmid-mediated gene therapy Blood, November 12, 2009; 114(20): 4373 - 4382. [Abstract] [Full Text] [PDF] C. H. Miao, B. R. Harmeling, S. F. Ziegler, B. C. Yen, T. Torgerson, L. Chen, R. J. Yau, B. Peng, A. R. Thompson, H. D. Ochs, et al. CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII-specific immune responses in plasmid-mediated gene therapy-treated hemophilia mice Blood, November 5, 2009; 114(19): 4034 - 4044. [Abstract] [Full Text] [PDF]

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